Polycystic ovary syndrome (PCOS) is a common disorder affecting 7% of reproductive age women marked by elevated androgen levels, oligo-anovulation, and polycystic ovarian morphology. PCOS is associated with hirsutism, acne, irregular menstrual cycles and infertility and causes an increased risk for obesity, the metabolic syndrome, and type 2 diabetes mellitus. Although PCOS is common and associated with significant morbidity, the etiology remains unknown. Neuroendocrine abnormalities-namely, increased luteinizing hormone (LH) and gonadotropin-releasing hormone (GnRH) pulsatility with relative follicle-stimulating hormone (FSH) deficiency-are commonly present in the disorder and contribute to its pathology. Progesterone (P) is thought to be the major regulator of GnRH synthesis and secretion. Indeed, women with PCOS demonstrate impaired hypothalamic sensitivity to P negative feedback, which is related to elevated androgens and is reversed by androgen-receptor antagonism. Hyperandrogenemia (HA) in adolescent girls is thought to be a precursor to PCOS. As with adult women with PCOS, girls with HA demonstrate elevated LH pulse frequency, and some HA adolescents also have impairment of LH pulse suppression by P, suggesting that abnormal LH (GnRH) pulsatility in these girls may be related to impaired negative feedback at the hypothalamus. This research proposal aims to better understand how neuroendocrine abnormalities arise in peripubertal girls with HA by studying the role of P in pubertal maturation in normal and HA adolescent girls in order to improve our understanding of normal and aberrant puberty. In doing so, this research may help guide future treatment-and perhaps prevention-of PCOS before its full expression in late adolescence and adulthood. The goal of this research is to assess (a) the role of P in directing GnRH secretion during normal pubertal maturation;(b) how this process may be altered in the setting of HA;and (c) how differential control of GnRH frequency depending on sleep status may explain observed patterns of GnRH secretion in girls with and without HA. Hence, this research proposal aims: Specific Aim 1: To determine whether physiologically-relevant P concentrations suppress LH pulse frequency in early pubertal girls. Specific Aim 2: To determine whether GnRH pulse frequency responsiveness to P negative feedback depends on sleep vs. wake status in late pubertal girls with and without HA. PUBLIC HEALTH RELEVANCE: Polycystic ovary syndrome (PCOS) is a common hormonal disorder marked by elevated male hormone levels, impaired ovulation and cysts on the ovaries that causes significant morbidity in adult women, including abnormal hair growth, acne, irregular menses, infertility, and an increased risk for diabetes, obesity and the metabolic syndrome. Likely, PCOS begins in puberty when girls develop pathologic and hormonal abnormalities similar to adult women with PCOS. This research will study the development of PCOS by determining the role of progesterone during pubertal maturation in normal and hyperandrogenemic adolescent girls with the hope that an improved understanding of hormonal abnormalities during puberty will aid in the prevention and treatment of the disorder.